Microduplication Overlapping YY1 at 14q32.2 Narrows the Candidate Interval for Cortical Malformation and Early-Onset Arterial Ischemic Stroke

YY1 encodes a zinc-finger transcription factor that regulates chromatin remodeling and plays a critical role in brain development and vascular remodeling. Its nuclear co-activator, YY1AP1, causes Grange syndrome, a systemic arteriopathy with impaired vascular smooth-muscle-cell proliferation and differentiation. Haploinsufficiency of YY1 causes Gabriele-de Vries syndrome, whereas the phenotypic consequences of increased YY1 dosage have not been well characterized. We describe a 3.6-year-old girl with prenatal ventriculomegaly, growth restriction, and complex brain malformations including septo-optic dysplasia, dysgenesis of the corpus callosum, diffuse cortical dysgyria, and focal cortical dysplasia. At 7 months, she presented with acute left hemiparesis due to an acute right striatal/internal capsule arterial ischemic stroke and a subacute left striatal infarct, without clear arteriopathy. Head CT demonstrated bilateral basal ganglia and subcortical white matter calcifications. Echocardiography revealed a patent foramen ovale (PFO) but was otherwise normal; metabolic and thrombophilia workups were normal. She later developed drug-resistant epilepsy requiring hemispherotomy. Examination showed mild microcephaly, hemiparesis, and moderate developmental delay. Chromosomal microarray identified a 14q32.2 duplication encompassing the first exon and promoter region of YY1, classified as a variant of unknown significance. This duplication is the smallest reported copy-number gain overlapping YY1 and therefore potentially narrows the candidate genomic interval, given the reported phenotype. The overlapping phenotype with larger distal 14q duplications that also include YY1 supports the hypothesis that increased YY1 dosage contributes to this phenotype, although other potential mechanisms are plausible. Identification of additional patients and functional studies are necessary to delineate the precise pathogenic role of YY1 in this complex observed phenotype.